Treating ALK-positive lung cancer--early successes and future challenges

Abstract

Rearrangements of the anaplastic lymphoma kinase (ALK) gene occur infrequently in non-small-cell lung cancer (NSCLC), but provide an important paradigm for oncogene-directed therapy in this disease. Crizotinib, an orally bioavailable inhibitor of ALK, provides significant benefit for patients with ALK-positive (ALK+) NSCLC in association with characteristic, mostly mild, toxic effects, and this drug has been approved by the FDA for clinical use in this molecularly defined subgroup of lung cancer. Many new ALK inhibitors are being developed and understanding the challenges of determining and addressing the adverse effects that are likely to be ALK specific, while maximizing the time of benefit on targeted agents, and understanding the mechanisms that underlie drug resistance will be critical in the future for informing the optimal therapy of ALK+ NSCLC.

Figure 1. ALK activation mechanisms

Activation of ALK signaling is rare in most adult tissues but is active in the development of the gut and nervous system. Activation of native ALK is via ligand-induced dimerization and resultant autophosphorylation. In drosophila the ligand for ALK is Jelly Belly, whereas in mammals pleiotrophin and midkine have been reported as ligands for ALK. ^,,, In most ALK+ cancers, ALK expression is re-instituted through the active promoter of a 5′ partner that fuses with the kinase-encoding region of ALK. The resulting fusion gene then generates a fusion protein that can dimerize via domains in the 5′ partner mimicking ligand induced activation. Rarely, mutations in the kinase domain of full length ALK can also promote primary oncogenic activation of ALK (Box 1). ALK phosphorylation results in activation of downstream signaling pathways including JAK/STAT, PI3K/AKT, and MEK/ERK, which can promote cell proliferation, differentiation, and provide anti-apoptotic signals.

Figure 2. Resistance mutation spectra in EGFR mutant, ALK+ and BCR-ABL+ cancers following treatment with relevant kinase inhibitors

The spectra of mutations found in EGFR mutation positive NSCLC, ALK+ cancers, and BCR-ABL+ chronic myeloid leukemia are shown. We hypothesize that activating mutations such as those found in EGFR constrain the resistance mutations to those that allow constitutive activation. In situations where activation of the kinase is driven by dimerization via a gene fusion partner (e.g., BCR-ABL and EML4-ALK), the kinase domain is less constrained and can accommodate a wider array of mutations. The gatekeeper mutation, which sits at a critical position in the ATP/kinase inhibitor pocket, in each oncogene is enclosed with a box. The predominant resistance mutation in EGFR following therapy with erlotinib or gefitinib is T790M (shown in larger font) with only rare reports of other resistance mutations occurring. ^- The most common resistance mutations in BCR-ABL are shown. T315I, the most frequent of these, only occurs <15% of the time. The true prevalence of the different ALK mutations that produce resistance to crizotinib in patients is still unknown but a single dominant form comparable to the status of T790M does not seem apparent among the patients studied to date. ^,,, Almost all of the resistance mutations found in patients have also been identified using in vitro screens. ^, Additional resistant mutations identified through these screens but not yet identified in patients are shown in blue. The asterisk denotes a mutation, F1174L, that was found in an IMT tumor with the RANB2-ALK gene fusion treated with crizotinib; all other mutations were found in ALK+ NSCLC patients.

Figure 3. Mechanisms of resistance to crizotinib in ALK+ NSCLC

Crizotinib resistance can be classified into two broad categories, those mechanisms that retain the dominance of ALK signaling and those that lose the dominance of ALK signaling either partially or completely. ALK-dominant resistance can occur through kinase domain mutations that inhibit crizotinib binding but permit ongoing constitutive activation of ALK. ^,, ALK dominant resistance also occurs through copy number gain of the ALK gene fusion, which may co-exist with resistance mutations. ^, Finally, poor penetration of crizotinib into the CNS may simply allow unaltered ALK+ cancer cells to grow because of inadequate local drug exposures. For resistance that degrades the dominance of ALK signaling, a second oncogene may become active via mutation or another mechanism co-existing with oncogenic ALK in the same cells. ^,,, Alternatively, true ALK independent resistance may arise through the outgrowth of clones that do not harbor an ALK gene fusion and contain a different activated oncogene (separate oncogene).